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PDBsum entry 3w33
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Transferase/transferase inhibitor
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PDB id
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3w33
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References listed in PDB file
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Key reference
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Title
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Design and synthesis of novel pyrimido[4,5-B]azepine derivatives as her2/egfr dual inhibitors.
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Authors
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Y.Kawakita,
M.Seto,
T.Ohashi,
T.Tamura,
T.Yusa,
H.Miki,
H.Iwata,
H.Kamiguchi,
T.Tanaka,
S.Sogabe,
Y.Ohta,
T.Ishikawa.
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Ref.
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Bioorg Med Chem Lett, 2013,
21,
2250-2261.
[DOI no: ]
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PubMed id
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Abstract
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A novel 7,6 fused bicyclic scaffold, pyrimido[4,5-b]azepine was designed to fit
into the ATP binding site of the HER2/EGFR proteins. The synthesis of this
scaffold was accomplished by an intramolecular Claisen-type condensation. As the
results of optimization lead us to 4-anilino and 6-functional groups, we
discovered 6-substituted amide derivative 19b, which has a
1-benzothiophen-4-yloxy group attached to the 4-anilino group. An X-ray
co-crystal structure of 19b with EGFR demonstrated that the N-1 and N-3
nitrogens of the pyrimido[4,5-b]azepine scaffold make hydrogen-bonding
interactions with the main chain NH of Met793 and the side chain of Thr854 via a
water-mediated hydrogen bond network, respectively. In addition, the NH proton
at the 9-position makes an additional hydrogen bond with the carbonyl group of
Met793, as we expected. Compound 19b revealed potent HER2/EGFR kinase (IC50:
24/36 nM) and BT474 cell growth (GI50: 18 nM) inhibitory activities based on its
pseudo-irreversible (PI) profile.
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